Notes

"Once development was ended, the fonts of growth and regeneration of the axons and dendrites dried up irrevocably. In the adult centers, the nerve paths are something fixed, and immutable: everything may die, nothing may be regenerated" - Ramon y Cajal, 1928.

Early Evidence for Cell Division in the Adult Brain Before

After

Plasticity and Repair of the Mammalian Brain

• Life-long neurogenesis in the adult hippocampus in mammals including humans. (still largely controversial).
• Involved in certain forms of learning and memory.
• Reduced and/or altered neurogenesis in neuro-psychiatric disease (e.g., depression, ageing).
• Areas involved in neurogenesis in adult human brains: dentate gyrus that is the entrance door to hippocampus, adult rodent brains: subventricular zone that migrate and differentiate in olfactory bulb cells.

In order to identify neural stem cells in the Dentate Gyrus of Hippocampus Intravital Imaging can be used, which allows to very deep within the tissue with a 2-photon technique. tdTOMATO is injected to identify the cells. This technique allows for the construction of a lineage tree of adult neural stem cells deriving from the same mother cell.

One mother and her daughters Things to look at:

• Stem cell dynamics
• Mode of cell division
• Migration and Integration
• Functional Properties (combined with GECIs)
• Self-Renewal Potential There is evidence suggesting long-term self-renewal, but there is also evidence suggesting the contrary, i.e., rather quick depletion.

Distinct Behaviour of Neural Stem Cells in the Hippocampus These two types of cells can be identified through molecular signature.

Diversity of Hippocampal Stem Cells

• Functional and molecular diversity of hippocampal neural stem cells.
• Long-term (>100 days) self-renewing stem cells exist in the adult mammalian hippocampus.
• How do they contribute to life-long neurogenesis?
• What are the stem cell dynamics with advancing age?

However, a main question is the prior history of a given cell and this can be investigated through iCOUNT.

Dynamic Regulation of Adult Neurogenesis The number of neurons generated is not static but dynamically regulated. Elements that induces an increase in the amounts of neurons generated are:

• Voluntary physical exercise doubles the amount of neurons generated in the hippocampus.
• Learning
• Housing of mice in an environmental enrichment, where they live in a much larger cohorts with more mouses.

One experiment demonstrating how enriched environment enhances learning based on Hippocampus is the Morris Water Maze. Indeed, mouses grown in an enriched environment showed much faster learning curves in finding the platform in the water maze compared to mouses grown in less "fancy" environments. Hence, there is some kind of correlation between increased hippocampus neurogenesis and performance in learning spatial locations, even though it has not yet been demonstrated a causality. Other examples, Cab driving increases hippocampal size: hippocampal volume correlates with the time spent behind the wheel. Students learning increases brain size.

There are however also negative regulators of neurogenesis (also involved with neurodegenerative diseases):

• Alcohol
• Stress: if you stress mice it dramatically reduces the amount of neurons generated in the hippocampus, which in turn has control over mood and can be implicated in depression. Indeed, studies demonstrated that antidepressant treatment are correlated with increased neurogenesis in adult rat hippocampus. Further studies, showed that there has to be neurogenesis happening in the hippocampus for antidepressants to work.
• Age
• Hit-Damage.

Irradiation Ablated Neurogenesis By using ionizing radiation, which divides cells (like those used in cancer therapy), dramatically reduces neurogenesis in the HC. In Santarelli et al. 2003, they studied mice that were treated with ionizing radiation to ablate neurogenesis in the hippocampus and then administered the antidepressant fluoxetine (Prozac). The results showed that ablation of neurogenesis in the hippocampus prevented the behavioral effects of fluoxetine, suggesting that neurogenesis in the hippocampus is required for the antidepressant effects of this drug.

Other approaches to ablate neurogenesis involve transgenic mice (using TK or suicide genes under the control of stem cell promoters) and local cell ablation (e.g., lentiviral vectors). All of these approaches are not perfect and present disadvantages, hence they are often used in combination to mitigate cons.

The Dentate Gyrus as a Pattern Separator The Dentate Gyrus represents very similar inputs distinctly within the brain. What it has been shown is that mice with decreased neurogenesis are impaired at spatial pattern separation.